Small particle engineering enables an active pharmaceutical ingredient (API) to be incorporated into a formulation for targeted drug delivery. Powder micronization can also be used to increase the dissolution rates of poorly water-soluble drugs.
Micronization procedures can modify particle size, porosity and density, and the API may be mixed with pharmaceutical excipients using small particle technologies to maximize delivery to the desired target for drug administration.
Particle formation technologies may be classified as either mechanical micronization processes or solution-based phase separation processes. Mechanical micronization methods include milling techniques such as that cited in U.S. Pat. No. 5,145,684. However, friction generated during these milling processes may lead to either thermal or mechanical degradation of the API. Spray drying, another common method used to micronize drug substances, requires extremely high temperatures, on the order of 150° C., to remove the solvent from the drug following atomization. The elevated temperatures may accelerate degradation of the active ingredient.
Solution-based techniques require less particle handling and are often easier to scale up than conventional milling techniques. Reduced particle handling results in higher yields and simplifies cleaning and sterilization procedures. Furthermore, solution-based processes can be continuous or semi-continuous unlike milling, which is typically a batch process.
Solution-based particle formation techniques involve the use of conventional liquids, or compressed gases, near-critical liquids or supercritical fluids functioning either as solvents, antisolvents, or cryogenic media for ultra-rapid freezing. These techniques involve phase separation of solvent and API either by evaporation, rapid expansion, change in solvent composition or solidification by freezing. The spray configuration in many of these processes produces atomized droplets with high surface areas. Thus phase separation and rapid nucleation result in small primary particles or highly porous microparticles.
Several solution-based phase separation techniques utilizing compressed fluids have been developed. Such micronization techniques typically employ liquid or supercritical fluid carbon dioxide as solvents or antisolvent, and involve atomization of a solution into the carbon dioxide from the vapor space above the carbon dioxide. The active ingredient is either contained in the solution or in the carbon dioxide itself. Precipitation of the active ingredient results in amorphous or crystalline powders. Such precipitation techniques are commonly referred to as, for example, precipitation with a compressed antisolvent (PCA), precipitation by rapid expansion from supercritical solutions (RESS), rapid expansion from supercritical to aqueous solution (RESAS) and are described in S. Palakodaty and P. York, Phase behavioral effects on particle formation processes using supercritical fluids, Pharm. Res., V. 16, 976-985 (1999); D. J. Dixon, K. P. Johnston and R. A. Bodmeier, Polymeric materials formed by precipitation with a compressed fluid antisolvent, AIChE J., V. 39, 127-139 (1993); R. Bodmeier, J. Wang, D. J. Dixon, S. Mawson and K. P. Johnston, Polymeric microspheres prepared by spraying into compressed carbon dioxide, Pharm. Res., V. 12, 1211-1217 (1995); B. Subramaniam, R. A. Rajewski and K. Snavely, Pharmaceutical processing with supercritical carbon dioxide, J. Pharm. Sci., V. 86, 885-890 (1997); and T. J. Young, S. Mawson, K. P. Johnston, I. B. Henriksen, G. W. Pace and A. K. Mishra, Rapid expansion from supercritical to aqueous solution to produce submicron suspensions of water-insoluble drugs, Biotechnol. Prog., V. 16, 402-407 (2000).
The success of the above-identified techniques depends heavily on the efficiency of atomization of the solution into the carbon dioxide. A disadvantage of such techniques when used with proteins and peptides is that many organic solvents used to dissolve the API also denature proteins and peptides. Therefore, such techniques may not lead to biologically active micronized protein powders. Even modified processes, utilizing an aqueous solution of proteins or peptides include the challenge of the low solubility of water in CO2, the need for large quantities of organic solvent, optimization of the mixing of multiple streams, and denaturation of the protein that can occur due to the exposure of the protein to the acidic CO2 (pH 3).
Another problem with the above-identified techniques is that they often require elevated temperatures to produce homogeneous precipitates, which elevated temperatures may enhance degradation of thermally labile drugs. Another disadvantage is the low solubility of most organic solids in supercritical CO2, since low drug loading into the supercritical CO2 results in low production rates of powders.
To dry the particles resulting from the above-identified solution methods, techniques include spray-freeze drying processes described in U.S. Pat. Nos. 3,721,725 and 5,208,998, and M. Mumenthaler and H. Leuenberger, Atmospheric spray-freeze drying: a suitable alternative in freeze-drying technology, Int. J. Pharm., V. 72, 97-110 (1991). A disadvantage of the above identified spray freeze-drying processes is that proteins can be easily denatured during freezing due to phase separation of water and its soluble components followed by ice crystal growth. Even modified spray freeze drying processes utilize expensive halocarbon refrigerants or result in unsuitably large particles.
It would be an advantage in the art of particle engineering for the pharmaceutical industry to provide a process which results in the formation of small particles without the problems associated with the above-identified prior art.